•Extrapyramidal Motor System

• Descending extrapyramidal paths receive input from other parts of motor system:

• From the cerebellum

• From the basal ganglia or “corpus striatum”

•Basal Ganglia or “Striatum”

• Caudate & putamen get input from cortex, thalamus & substantia nigra, a midbrain motor area

• They send commands to globus pallidus which sends them on to the motor portions of thalamus & brainstem

• Very interconnected system with lots of feedback loops

•Basal Ganglia or Striatum

• Interconnected set of nuclei (gray matter) buried within the cerebral hemispheres that have primarily motor functions

• Best known components:

• Caudate nuclei (“tail shaped nuclei”)

• Putamen (“seashell”)

• Globus pallidus (“pale globe”)

•Functions

• The basal ganglia are important for:

• Initiating or starting motor programs – often multiple programs at once

• Inhibiting undesired movements; terminating voluntary movements

•Parkinson’s Disease
(paralysis agitans or shaking palsy)

• About 1% of those over 50 have PD (~ 1,000,000 total in US; 55,000 new cases/yr; 90% cases occur after age 60)

• Progressive deterioration of major DA input to basal ganglia- the “nigrostriatal pathway” from substantia nigra to the “striatum”

• We lose about 4% of those DA neurons/decade, but those with PD have accelerated loss (70% or more gone)

• Results in difficulty initiating movements & tremor

• The nigrostriatal path sends DA messages from the substantia nigra to the basal ganglia.

•Classic PD Symptoms

• Worsening bradykinesia & akinesia

• Rigidity; clumsiness, decreased postural stability so tends to fall

• “Pill-rolling” tremor-at-rest

• Reduction in movement is also seen in lack of facial expression & blinking; shuffling walk without assoc. arm movements; soft, halting, monotone voice; slow blinks; small writing; feeling stuck or frozen

•Possible Causes

• Environmental toxin of some sort (industrial heavy metals, pesticides, “free radicals” currently under study)

• Genetics (especially in those who get PD at an early age)

• Brain trauma may increase your risk

•Treatments

• Increase DA production with l-dopa/carbidopa (Sinemet)

• Problems: l-dopa induced dyskinesias and loss of effectiveness over time

• Others: DA agonist (bromocriptine/Parlodel or pergolide/Permax, or newer, better Mirapex, Requip) or DA releasor (amantadine/Symmetrel)

• Eldepryl/Deprenyl (selegiline) to decrease DA breakdown and slow loss of neurons

• Anti-ACh drugs (Artane, Cogentin) can help restore chemical “balance” of basal ganglia

•When Drug Therapy Fails

• When drug effectiveness declines, exp. options include:

• Pallidotomy; thalamotomy (Michael J. Fox)

• Deep brain (thalamic) stimulation

• Transplant of DA producing cells

•Parkinson’s Disease Update

• Although PD is thought of as a motor disorder, the decline in DA also produces cognitive and emotional changes in some

• “bradyphrenia” (cognitive slowing); decreased attention

• “frontal lobe” symptoms (disinhibition of behavior, poor judgment and planning)

• Major depression

• Full-blown dementia in ~50% (associated with neuropathological sign called Lewy bodies)

• PD treatment, on the other hand, can produce hallucinations and other symptoms of psychosis

•Impairment of the Inhibitory Functions of the BG

• Dyskinesias – involuntary movements

• Chorea (“dance-like”) – quicker irregular movements

• Athetosis – slower writhing, twisting movements

• Dystonias – abnormalities of excessive muscle tone

•Huntington’s Disease

• Transmitted by a dominant gene on chromosome 4 (about 30,000 US cases with 150,000 at risk kids)

• Deterioration of striatum produces involuntary chorea, athetosis & other motor difficulties

• Cortical deterioration causes progressive & debilitating dementia, aggressiveness, mood swings, depression, psychosis

• Death due to health complications in 15-20 yrs

•Huntington’s Disease

• Bad gene has excess “CAG repeats” (more than 36-250 instead of usual 29 or fewer) resulting in an abnormal form of protein known as huntingtin.

• The more repeats, the earlier symptoms appear.

• # of repeats can increase across generations, especially in kids inheriting gene from father

• Brain damage may be due to decrease in normal protective huntingtin + adverse effects of abnormal protein on critical growth factors keeping cells alive.

• Also looking at effects on excitotoxins & glucose metabolism.

•Treatments for HD

• Genetic testing to identify presence of the gene

• Involuntary movements may be decreased by DA blockers (antipsychotics)

• New drugs being tried to delay progression:

• Rilutek (riluzole), Neurontin (gabapentin) decrease glutamate transmission

• Rapamycin (transplant drug) speeds elimination of abnormal protein

• Growth factor supplementation being studied

• Experimentation with brain cell transplants/surgeries is underway

•Tourette Syndrome

• Another *hereditary BG disorder characterized by involuntary movements

• Multiple motor tics - simple tics of face or limbs and/or more organized complex tics (touching, grimacing, pinching, poking, adjusting, hitting, jumping, kissing, throwing, gestures) plus:

• Phonic or vocal tics - both simple (throat-clearing, coughing, hiccuping, grunting, yelping) and/or complex tics (actual words, coprolalia, echolalia, palilalia, assuming different voices, talking to oneself in different voices)

• Seems to affect frontal lobe- BG connection that is important for our ability to inhibit actions

•Tourette Syndrome

• 40% report “sensory tics” – uncomfortable sensations that may be a reason for some of the involuntary movements

• Some degree of suppressibility, but individual experiences increased tension until tic is released

• Pattern of tics changes & waxes & wanes with changes in stress, anxiety, fatigue.

• Treated with DA blockers (antipsychotics). Milder tics may respond to NE agonist clonidine.

• Majority experience decreased tics as adults.

•Link with Other Disorders

• ~50-60% also suffer OCD (others estimate that up to 90% experience some involuntary touching compulsions, ritualistic behaviors, intrusive thoughts)

• ~50-90% show evidence of ADHD as well; first signs of GTS are usually impulsive, hyperactive behaviors (before tics appear)

• About 30% have learning disabilities, emotional lability, rage, aggressiveness; 40-50% depressed

• Evidence suggests a single gene with sex-linked, varied forms of expression of disinhibition

• 50-73% concordance in identical twins vs 8-22% in fraternal twins